Glioblastoma (GB) is the most common primary brain cancer with a 5 year survival rate of <15%, even with the most aggressive therapies. Malignant glioma cells are highly invasive and their efficient infiltration into adjacent normal brain tissue prevents complete surgical removal and limits the dosing of radiation and chemotherapeutic drugs. Unfortunately, local chemotherapy, provided by either biodegradable polymer implants or convection-enhanced delivery, has had limited clinical success; in part due to inefficient delivery of therapeutics to distant invading tumor cells. Fibroblast growth factor-inducible 14 (Fn14), a member of the tumor necrosis factor (TNF) receptor superfamily, is a promising molecular target for GB therapy. High Fn14 expression correlates with higher brain tumor grade and poor patient outcome, and is found in both migrating glioma cells in vitro and invading glioma cells in vivo. Hence, a delivery strategy designed to target Fn14+ tumor cells is a promising approach for treating distant invading tumor cells. Our pilot data show that gene vectors with bio-inert surfaces (via extremely dense PEG coatings) provide improved penetration and distribution in brain tissue, minimize non-specific binding, and therefore have a greater potential for cell-specific targeting in the brain. Our overall hypothesis is that Fn14-targeted gene vectors will suppress brain cancer invasion by delivering therapeutic gene constructs into the regions of the brain that contain infiltrating tumor cells and effectively inhibiting Fn14 signaling in invading Fn14+ glioma cells. This hypothesis will be tested in the following specific aims: (1) synthesize and characterize Fn14-targeting gene vectors and assess their Fn14 targeting, cellular trafficking, and in vitro gene expression in Fn14+ glioma cells, (2) using optimized gene vectors from Aim 1, evaluate brain tissue penetration and particle distribution in vivo, and (3) using therapeutic version of gene vectors from Aim 2, evaluate inhibition of Fn14 signaling and suppression of glioma cell invasion ex vivo and in vivo. These studies will provide an important next step in the application of brain- penetrating delivery technologies; specifically, directly targeting treatments to the key infiltrating tumor cells not accessible with surgery. Our next step would include: (1) identifying optimum therapeutic gene and cellular pathway targets, and (2) augmenting particle delivery and dispersion using convection-enhanced local delivery and focused ultrasound mediated systemic delivery.